Autoimmune diseases are broadly characterized by the immunological loss of self-tolerance. In systemic lupus erythematosus (SLE), a canonical autoimmune disease, a traditional hallmark is the persistence of T and B cells that are aberrantly reactive to self-antigens such as nucleic acids and nuclear proteins; these T and B lymphocytes promote the production of pathogenic autoantibodies which deposit in tissues and prime inflammatory damage (Shlomchik, et al., Nat Rev Immunol, 1(2): 147-53 (2001); Rahman, et al. N Engl J Med, 358(9):929-39 (2008)). The contribution of innate antigen presenting cells has recently been elucidated.
Dendritic cells and macrophages have been shown to contribute to lupus pathology by producing proinflammatory cytokines (Blanco, et al., Science, 294(5546): 1540-3 (2001); Triantafyllopoulou, et al., Proc Natl Acad Sci USA, 107(7):3012-7 (2010)) and promoting expansion of autoreactive T and B cells (Teichmann, et al., Immunity, 33(6):967-78 (2010)).
Current methods used to treat autoimmune diseases have traditionally relied on the chronic administration of hydrophobic drugs (Monneaux, et al., Arthritis Res Ther, 11(3):234 (2009)) or, more recently, biological agents (proteins and neutralizing antibodies) (Ronnblom, et al., Nat Rev Rheumatol, 6(6): 339-47 (2010); Navarra, et al., Lancet, 377(9767):721-31 (2011); Sfikakis, et al., Curr Opin Rheumatol, 17(5): 550-7 (2005)) which inhibit the proliferation or activation of lymphocytes. The conventional administration of pan-immunosuppressive small molecule therapies, which are often achieved with hydrophobic drugs such as cyclophosphamide, azathioprine, or mycophenolate mofetil (MMF), provides therapeutic immunosuppression by blunt reduction of total immune cell numbers. This pan-suppressive effect can lead to organ toxicity or lymphopenias and anemia, and render human patients more susceptible to opportunistic infections (Lee, et al., Lupus, 19(6):703-10 (2010); Moroni, et al., Clin J Am Soc Nephrol, 1(5):925-32 (2006)). Biological agents which deplete B cells or block T cell costimulatory signals may provide a more refined, cell-specific approach to immunosuppression, but as a stand-alone monotherapy they may be ineffective in attenuating autoimmunity from innate antigen presenting cells.
An ideal therapeutic strategy could combine the pan-suppressive effects of small molecule therapies with targeting specificity to the immune cells implicated in lupus pathogenesis. Nanoparticles have been actively explored for therapeutic use in other diseases such as cancer (Blanco, et al., Cancer Sci, 102(7): 1247-52 (2011)) and infectious pathogens (Look, et al., Adv Drug Deliv Rev, 62(4-5):378-93 (2010)). These nanoparticle drug delivery systems can be loaded with therapeutic compounds with several different methods, and their use in vivo can improve the bioavailability of therapeutic compounds and to specifically target tissues or cells of therapeutic interest (Fahmy, et al., Materials Today, 8(8): 18-26 (2005)). Few therapeutic strategies have extensively explored the efficacy of nanoparticles as a drug delivery vehicle for achieving therapeutic immunosuppression in lupus. To date, published reports regarding nanoparticles and lupus are limited to studies of nanoparticles that are designed to traffic to relevant sites of lupus pathology, namely the kidney (Scindia, et al., Arthritis Rheum, 58(12):3884-91 (2008); Serkova, et al., Radiology, 255(2):517-26 (2010)), but no studies have demonstrated actual therapeutic drug delivery with these nanoparticle systems. Thus, little is known about how nanoparticles may interact with different immune cell sets in lupus, and if these interactions could be exploited to improve lupus immunotherapies.
Several types of nanoparticle systems, liposomes and synthetic polymeric matrix formulations are commonly used. Several nanoparticle platforms are potential candidates for this purpose. Generally these platforms can be classified as either vesicular in nature (such as liposomes) or composed of solid biodegradable matrices (such as polyester-based nanoparticles). Liposomes are easily modified for encapsulation of small hydrophilic molecules, and even proteins, but the stability of these formulations and the release profiles of encapsulated agents can be poor (Maurer, et al., Expert Opinion on Biological Therapy, 1(6):923-947 (2001)). Biodegradable solid particles such as those fabricated from poly(lactic-co-glycolic acid) (PLGA), are highly stable and have controllable release characteristics, but pose complications via induction of maturation of dendritic cells (Yoshida, et al., J Biomed Mater Res A, 80(1):7-12 (2007)) and degradation into acidic byproducts that may promote inflammation (Shive, et al., Adv Drug Deliv Rev, 28(1):5-24 (1997)).
No effective treatment for lupus other than generalized immunosuppression has been found.
It is therefore an object of the present invention to provide compositions for treating lupus with greater selectivity and efficacy.
It is also an object of the present invention to provide a method for treatment of lupus with greater selectivity and efficacy.